Drosophila stem cell niches provide useful models for understanding mammalian stem cell behavior. Great progress has been made in defining principles that control constitutively active niches such as the germ line and intestine. However, the quiescent stem cell niche that can regenerate a tissue in response to injury is less well understood. Our studies have recently led to the identification of a novel gastric stem cell (GSSC) in the adult Drosophila stomach. GSSCs exhibit a number of unique behaviors. Significantly for this proposal, gastric stem cells are normally quiescent, but are rapidly induced to regenerate the entire gastric epithelium in response to tissue damaging injury. Our preliminary data indicate that GSSCs are controlled by conserved signaling pathways, which have been implicated in mammalian and invertebrate stem cell niches, including those found in the gastrointestinal tract. These observations raise the central hypothesis that epithelial regeneration in the stomach is achieved through a region-specific niche program, which adapts the GSSC to a unique stomach physiology. In Aim 1 we propose to test the mechanism of gastric stem cell maintenance in a quiescent niche. In Aim 2 we propose to characterize the signals that regulate gastric stem cell quiescence. In Aim 3 we propose to address the basis of cell fate specification in a tri-potent gastric lineage. These questions are currently difficult to address in mammals, as the principle gastric stem cells of the stomach have not yet been identified. Thus, we propose to use Drosophila as a model to dissect the mechanisms controlling a quiescent gastric stem cell niche. PUBLIC HEALTH RELEVANCE: Stem cells have enormous potential to impact the treatment and cure of human disease. Accurate models of how stem cells are regulated in their native environments are now needed to effectively utilize stem cells in regenerative medicine and cell-based therapies. Studies in Drosophila have great predictive power for humans because of the unifying principles of biological conservation that exist at both the cellular and molecular levels